TrkB.T1 as a Genetic Disease Modifier of Muscular Dystrophy

TrkB.T1 作为肌营养不良症的遗传疾病修饰剂

• 批准号: 7938056
• 负责人: SUSAN G DORSEY
• 金额: $ 109.68万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7938056
• 关键词: Acute; Age; Becker Muscular Dystrophy; Biopsy; Biopsy Specimen; Brain-Derived Neurotrophic Factor; Caring; Cells; Cessation of life; Clinical; Clinical Research; Complex; Coupling; Defect; Disease; Disease Progression; Distal; Duchenne muscular dystrophy; Dystrophin; Event; Facioscapulohumeral; Family; Fiber; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Goals; Government; Health Care Costs; Hereditary Disease; Inherited; Injury; Investigation; Knockout Mice; Ligands; Limb structure; Mediating; Modeling; Molecular; Mus; Muscle; Muscle Cells; Muscle Proteins; Muscle Weakness; Muscle function; Muscular Dystrophies; Natural regeneration; Neonatal; Neurotrophic Tyrosine Kinase Receptor Type 2; Pathology; Patients; Performance; Physiological; Process; Protein Isoforms; RNA Splicing; Regulation; Research Personnel; Research Priority; Resistance; Role; Sampling; Severity of illness; Signal Transduction; Skeletal Muscle; Staging; Tetanus Helper Peptide; Time; Tissues; Transforming Growth Factor beta; Transgenic Mice; Up-Regulation; Work; base; clinical phenotype; gain of function; gene therapy; improved; in vivo; mdx mouse; mouse model; muscle degeneration; muscle regeneration; muscle strength; neuromuscular; new therapeutic target; postnatal; prevent; public health relevance; receptor; repaired; repository; research study; therapeutic target; ward

DESCRIPTION (provided by applicant): The muscular dystrophies are complex genetic diseases characterized by inherited or sporadic defects in genes that encode muscle proteins. Although Duchenne (DMD), Becker, limb girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss are the most common muscular dystrophies, the total number of diseases characterized as muscular dystrophies exceeds thirty (MD-CARE_Act, 2008). Common to all of the muscular dystrophies is progressive skeletal muscle weakness and the death of muscle cells and tissue. Although the genetic basis for most of the dystrophies is known, a disease cure may still be years away. This fact has increased the research priority mandate from researchers, family support organizations (G¿nter Scheuerbrandt, 2008) and the government (MD-CARE_Act, 2008) to identify critical "downstream" events in the dystrophic process that can be therapeutically targeted to halt or slow the disease progression until a genetic (gene therapy) cure is realized. Transforming Growth Factor beta (TGF-() signaling is pathogenic in dystrophy (Chen et al., 2005). Recent work by our group showed that antagonizing TGF-( normalizes muscle repair and restores muscle function in the well-described mdx mouse model of muscular dystrophy (Cohn et al., 2007). To identify critical downstream transcriptional events following increased TGF-( signaling, we generated a tet-repressible muscle-specific TGF-( transgenic mouse and we find that over-expression of TGF-( causes muscle weakness (Hoffman and Chen, unpublished). In related preliminary studies examining gene expression in clinical DMD muscle biopsy samples we show that the truncated form of the Brain-derived Neurotrophic Factor (BDNF) receptor, trkB.T1, but not other trkB isoforms, is highly associated with TGF-( expression (Hoffman et al., unpublished). Further investigation revealed that genetic deletion of trkB.T1 (Dorsey et al., 2006) results in a gain-of-function in neuromuscular performance, increased muscle contractility and resistance to eccentric muscle injury (Dorsey and Ward, unpublished). Complementary gene expression studies showed that TGF-( and its receptor were downregulated in trkB.T1-/- muscle. An intercross between trkB.T1-/- and mdx mice to reduce trkB.T1 expression in vivo resulted in a complete rescue of dystrophy-associated loss of skeletal muscle contractility (Dorsey and Ward, unpublished), similar to targeting TGF-( (Cohn et al., 2007). We hypothesize that trkB.T1 may be a significant disease modifier of muscular dystrophy and could represent a novel therapeutic target for its treatment. PUBLIC HEALTH RELEVANCE: Muscular dystrophy is a disease that causes significant muscle weakness that gets worse over time. Although we know about the genetic causes of the disease, we still do not have ways to slow down muscle weakness or make muscles stronger once they become weak. From our preliminary studies, we have an idea that two molecules that function in muscle cells to regulate muscle strength might be able to be manipulated to improve muscle function in patients with muscular dystrophy. This study will try to figure out why these two molecules may be possible therapeutic targets. Our goal is to prevent, improve, or restore muscle function in patients with muscular dystrophy.

描述（由申请人提供）：肌营养不良症是一种复杂的遗传性疾病，其特征是编码肌肉蛋白的基因存在遗传性或散发性缺陷。虽然杜氏肌萎缩症（DMD）、贝克肌萎缩症、肢带肌萎缩症、先天性肌萎缩症、面肩肱肌萎缩症、肌强直性肌萎缩症、眼咽肌萎缩症、远端肌萎缩症和艾默-德莱弗斯肌萎缩症是最常见的肌萎缩症，但以肌萎缩症为特征的疾病总数超过30种（MD-CARE_Act, 2008）。所有肌肉萎缩症的共同特点是进行性骨骼肌无力以及肌肉细胞和组织的死亡。虽然大多数营养不良症的遗传基础是已知的，但要治愈这种疾病可能还需要数年时间。这一事实增加了研究人员、家庭支持组织（G¿intter Scheuerbrandt, 2008）和政府（MD-CARE_Act, 2008）的研究优先任务，以确定营养不良过程中的关键“下游”事件，这些事件可以通过治疗靶向来阻止或减缓疾病进展，直到实现遗传（基因治疗）治愈。转化生长因子β (TGF-)信号在营养不良中起致病作用（Chen et al., 2005）。我们小组最近的工作表明，在描述良好的mdx肌营养不良小鼠模型中，拮抗TGF-(可使肌肉修复正常化并恢复肌肉功能（Cohn et al., 2007）。为了确定TGF-(信号传导增加后的关键下游转录事件，我们产生了一个可抑制的肌肉特异性TGF-(转基因小鼠，我们发现过度表达TGF-（会导致肌肉无力）（Hoffman和Chen，未发表）。在临床DMD肌肉活检样本中检测基因表达的相关初步研究中，我们发现脑源性神经营养因子（BDNF）受体trkB的截断形式。T1，而不是其他trkB亚型，与TGF-(表达高度相关（Hoffman et al.，未发表）。进一步研究发现trkB基因缺失。T1 （Dorsey et al., 2006）导致神经肌肉性能的功能获得，肌肉收缩性增加和对偏心肌损伤的抵抗力（Dorsey和Ward，未发表）。互补基因表达研究显示TGF-（及其受体）在trkB中下调。T1 - / -肌肉。trkB之间的交叉。T1-/-和mdx小鼠减少trkB。体内T1表达可完全挽救营养不良相关的骨骼肌收缩力丧失（Dorsey and Ward，未发表），类似于靶向TGF-(Cohn etal ., 2007)。我们假设trkB。T1可能是肌营养不良的重要疾病调节剂，可能是治疗肌营养不良的一个新的治疗靶点。